This proposal seeks to investigate the broad hypothesis that hormone therapy (HT) composed of the two female sex steroid hormones estrogen and progesterone may be effective in preventing the progression of Alzheimer's disease (AD) in women. While estrogen's many beneficial effects in the brain have been well established, the effects of progesterone, both alone and in combination with estrogen, are currently unclear and under-investigated. The Women's Health Initiative study raised several questions regarding the actions of progestins in the brain and the efficacy of HT in lowering the risk of AD in post-menopausal women such as the effects of a) estrogen alone or in combination with progesterone, b) the use of a continuous or cyclic progestin dose, and c) the mechanism by which hormones induce their effects. In the specific aims outlined below, I propose experiments that will address each of these questions using a transgenic mouse model of AD. These results will provide crucial insight into progesterone's unknown effects in the brain and will aid the imperative need for research investigating the effects of estrogen and progesterone on AD pathology. Since over 4.5 million Americans suffer from AD, this issue is of critical importance. Understanding the effects of estrogen and progesterone in the brain is essential for optimization of hormone therapy for postmenopausal women and the prevention and treatment of Alzheimer's disease. Aim 1: Does estrogen regulate AD-like pathology through a receptor-dependent mechanism? Based on the wealth of evidence establishing that many of estrogen's neuroprotective actions in the brain are mediated through estrogen receptors, I hypothesize that estrogen regulates AD-like pathology through a receptor-dependent mechanism. To test this hypothesis, I will use the triple transgenic mouse model of AD to determine if selective estrogen receptor agonists and antagonists differentially modulate AD-like pathology. Furthermore, I will investigate two candidate downstream pathways of estrogen action by measuring markers for both amyloid precursor protein (APP) processing and beta-amyloid degradation in these mice. Aim 2: How does progesterone influence estrogen regulation of AD-like pathology? Progesterone has demonstrated varying effects in the brain and modulates estrogen function. I hypothesize that various paradigms of progesterone treatment differentially modulate the beneficial effect of estrogen on AD-like pathology. Again, using the triple transgenic mouse model of AD, I will determine if progesterone modulates estrogen regulation of AD-like pathology, if the length of progesterone exposure influences this effect, and if progesterone modifies estrogen's activity by modulating estrogen receptor expression in the brain. [unreadable] [unreadable]